medwireNews: The benefit offered by olaparib in metastatic castration-resistant prostate cancer (mCRPC) is attenuated when a more active standard of care is used as the comparator, suggests a network analysis of the PROfound and CARD trials.
The researchers explain that the PROfound results led to the US FDA approval of the PARP inhibitor olaparib for patients with homologous recombination repair (HRR)-deficient mCRPC and progressive disease after a prior androgen signaling inhibitor (ARSi).
They note, however, that concerns have been raised regarding the trial’s control group treatment, namely switching ARSIs, which “has been reported to have PSA50 (prostate-specific antigen decline ≥50%) response rates as low as 1%.”
The team therefore used a network analysis approach to compare olaparib with a more active standard of care, cabazitaxel, using data from the PROfound and CARD trials, respectively, both of which had ARSi switch as the control.
A frequentist meta-analysis showed that among men with BRCA1/2 or ATM mutations (cohort A of PROfound) olaparib was associated with a significant improvement in radiographic progression-free survival (PFS) relative to cabazitaxel (hazard ratio [HR]=0.63), especially among those who had previously received taxanes (HR=0.52).
These findings were supported by a Bayesian meta-analysis, which estimated a 70% and 78% probability of superiority for olaparib over cabazitaxel in the overall cohort and the prior taxane subgroup, respectively.
However, radiographic PFS was not significantly prolonged with olaparib versus cabazitaxel among participants who harbored variants in 12 other HRR genes (PROfound cohort B; nonsignificant HR=1.63), and the Bayesian analysis showed an 83% probability that cabazitaxel was superior in these patients.
Overall survival did not differ significantly between treatments in any of the groups in the frequentist analysis, but the Bayesian analysis estimated a 60% probability of superiority for olaparib among taxane-treated patients with BRCA1/2 or ATM mutations, whereas there was an around 75% probability that cabazitaxel was superior among patients with other HRR variants and the full study cohort.
“In this study, the benefit associated with olaparib was reduced, eliminated, or inferior in specific subgroups of patients when treatment outcomes were compared with a more active standard of care,” summarize Christopher Wallis (Vanderbilt University Medical Center, Nashville, Tennessee, USA) and colleagues.
Noting that patients with other HRR variants “may have worse outcomes” with olaparib, they stress the need for national guidelines to reassess recommendations for this group.
Writing in a research letter to JAMA Network Open, Wallis et al highlight the limitations of their analysis, such as “the indirect nature and transitivity due to differences in the inclusion criteria of the 2 trials, unknown differential response of cabazitaxel to molecular subgroups used in PROfound, wide confidence intervals due to limited patient numbers, and the effect of crossover allowed in both trials.”
Nevertheless, they believe that “these hypothesis-generating data suggest reconsideration of the role of olaparib, and for which patients, in the mCRPC treatment armamentarium.”
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JAMA Netw Open 2021; 4: e2110950